Biochemical and physiological data support the role of nuclear T3-receptors as mediators of thyroid hormone action in many tissues. The basic assumptio for this study is that nuclear T3-receptors mediate the effect of thyroid hormones on biochemical lung maturation. Thus the objective is to correlate the uptake of thyroid hormones and subsequent occupancy of the nuclear receptors with stimulation of surfactant phospholipid synthesis. Thyroid hormones influence lung maturation and surfactant production in the fetus. Thyroxine deficiency retards, whereas thyroid hormone administration accelerates the morphological and biochemical development of fetal lung both in vivo and in vitro. However, the mechanism of thyroid hormone action is unknown. Study of thyroid hormone interaction with and influelnce on developing lung will help define the molecular mechanisms by which these hormones regulate cellular processes in lung and other tissues. Explant cultures of human fetal lulng will be grown in the presence of unlabeled or (125I)-labeled thyroid hormones and the nuclei isolated with Triton X-100. The kinetics of hormone uptake by and dissociation from nuclei, and the hromonal effects on (3H)-choline incorporation into phospholipid and glycogen depletion will be compared. Nuclear occupancy, estimated by the 37-2 centigrade difference method and dose-respone curves, will be compared to the dose-response curves for hormonal stimulation of (3H)-choline incorporation. Occupancy of nuclear receptors by endogenous thyroid hormones and the identity of the hormonal species (T3, T4, rT3) will be determined by radioimmunoassay of nuclear extracts. Nuclei will also be examined for the presence of unique rT3-binding sites, suggested by preliminary data. Protection of occupied receptors from temperature-inactivation in explant cultures will be investigated using L-T3 and other thyroid hormone analogs. These studies will provide information on the relationships between nuclear occupancy, phospholipid synthesis and the effective thyroid hormone species. This knowledge will contribute to potentially useful application of these hormones as therapeutic agents in the prevention and treatment of respiratory distress syndrome.